The goal of this project is to use rodent models to elucidate the mechanisms underlying the behavioral effects of hallucinogenic drugs of abuse, including MDMA ("Ecstasy"), LSD, phencyclidine (PCP), and ketamine ("Special K"), as well as natural products used in recreational, ritual, or religious contexts, including psilocybin mushrooms (psilocin) and Ayahuasca tea (DMT, 5MeODMT, harmaline). Based on the profound effects of hallucinogens on responses to sensory and emotional stimuli, the two complementary behavioral paradigms used to assess drug effects in both rats and mice include prepulse inhibition of the startle response, an operational measure of sensorimotor gating, and a multivariate profile of exploratory and locomotor responses provided by both rat and mouse Behavioral Pattern Monitor systems. These computerized systems assess activity, exploration, and behavioral organization - three major aspects of rodent behavior in an open field. The project has five specific aims. Aim 1 is to further characterize the contributions of specific serotonin (5HT) and dopamine receptors to the behavioral effects of the 5HT releaser MDMA in genetically engineered mice lacking specific subtypes of 5HT or dopamine receptors. Aim 2 is to characterize and identify the respective contributions of the 5HT1A and 5HT2A receptors to the behavioral effects of the synthetic equivalent of Ayahuasca ("Pharmahuasca") in rodents, using pharmacological and genetic manipulations. Aim 3 is to assess the respective contributions of 5HT1A and 5HT2A receptors to the behavioral effects of glutamatergic hallucinogens, and thereby evaluate the new hypothesis that the effects of both serotonergic and glutamatergic hallucinogens are mediated by some common mechanisms. Aim 4 is to use similar approaches to test for common contributions of metabotropic glutamate receptors, particularly mGluR5, to the behavioral effects of glutamatergic and serotonergic hallucinogens. Aim 5 will initiate a new line of research examining the contributions of the major stress-related hormone, corticotropin releasing factor (CRF), to the behavioral effects of hallucinogens. Studies will explore the exaggerated responses to threatening or stressful aspects of novel environments produced by serotonergic hallucinogens in rodents, which are similar to the fear and stress responses produced by LSD in humans. This research is designed to elucidate the neurobiological mechanisms responsible for the acute effects of hallucinogens, which presumably lead to the recreational use of these drugs of abuse.